The present invention is related to a process to highly enantioselectively and highly diastereoselectively prepare optically active xcex2-amino alcohols useful as an intermediate for synthesizing pharmaceutical active ingredients and agricultural chemicals at a high yield by using a racemic xcex1-aminocarbonyl compound as the starting material.
Optically active xcex2-amino alcohols are considered as an important intermediate for synthesizing pharmaceutical active ingredients and agricultural chemicals. As references wherein processes for preparing such optically active xcex2-amino alcohols have been disclosed, the followings may be given as examples.
1 Process in which the reaction of xcex1-(substituted-amino)aldehyde and a metal reagent is employed.
i) JP laid-open No. 50-137911 gazette
* (Anti-isomer/Syn-isomer=4.3-2.5/1)
ii) J. Org. Chem., 55, 1439 (1990)
2 Process in which diastereoselective reduction of optically active xcex1-amino ketone is employed.
Tetrahedron. Lett., 35, 547 (1994)
3 Process in which diastereoselective reduction of optically active xcex1-alkoxyimine is employed.
J. Chem. Soc. Chem. Commun., 746 (1987)
4 Process in which diastereoselective hydrogenation of xcex1-amino-xcex2-keto acid is employed.
i) J. Am. Chem. Soc., 111, 9134 (1989)
ii) J. Am. Chem. Soc., 115, 144 (1993)
5 Process in which asymmetric reduction of keto oxime is employed.
JP laid-open No. 10-45688 gazette
Among the processes in the past as described above, the diastereoselctivity in the processes {circle around (1)} and {circle around (5)} are low. The processes {circle around (2)} and {circle around (3)} require to prepare the raw material for the optically active compound beforehand and are thus complicated, the process {circle around (4)} allows to prepare highly diastereoselective optically active amino alcohol when a substrate containing a functional group, such as carboxyl, in the molecule is used, however, it is difficult to prepare optically active compounds according to the process {circle around (4)} when simple amino alcohol containing no functional group in the molecule is used.
Because of the difficulty as described above, development of selective production process of optically active xcex2-amino alcohols by using the racemic modification, which is more commonly-useful and can produce the desired products at high yields, has been desired.
In the present invention, the syn-isomer is defined as the one having a steric configuration wherein both amino group and hydroxy group to be respectively substituted in a vertical direction of carbon atoms in chain face toward the same plane when the carbon atoms in chain are fixed as the central axis and the steric configuration is laid in a horizontal direction, while the anti-isomer is defined as the one having a steric configuration wherein both amino group and hydroxy group face toward the contrary planes with each other.
It is an object of the present invention to provide practical manufacturing process for optically active xcex1-amino alcohols by using one of widely-available racemic xcex1-aminocarbonyl compounds as the starting material.
For achieving the object described above, the present invention provides a process for the preparation of optically active xcex2-amino alcohols represented by the general formula (2); Raxe2x80x94C*H(OH)xe2x80x94C*H(Rb)xe2x80x94Rc, wherein Ra and Rc are each independently hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted aralkyl or optionally substituted aryl, Rb is one member selected from among groups represented by the following general formulae; (3) R1CO(R2)Nxe2x80x94, (4) R1CO(R1xe2x80x2CO)Nxe2x80x94, (5) R1CO(R1xe2x80x2SO2)Nxe2x80x94, and (6) R1SO2(R2)Nxe2x80x94, wherein R1, R1xe2x80x2 and R2 are each independently hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted cycloalkoxy, optionally substituted alkenyl, optionally substituted aralkyl, optionally substituted aralkyloxy, optionally substituted aryl or optionally substituted aryloxy, or alternatively R1 and R2 or R1 and R1xe2x80x2 may be united to form a five- to eight-membered nitrogenous heterocycle, and C* is an asymmetric carbon atom, characterized by reacting a racemic xcex1-aminocarbonyl compound represented by the general formula (1); Raxe2x80x94COxe2x80x94CH(Rb)xe2x80x94Rc, wherein Ra, Rb and Rc are each as defined above, with hydrogen or a hydrogen donor in the presence of an optically active transition metal compound and a base.
In the preparation process of optically active xcex2-amino alcohols according to the present invention, it is preferable that the optically active transition metal compound is a homogeneous system optically active hydrogenation catalyst.
And, it is further preferable that the homogeneous system optically active hydrogenation catalyst is an optically active transition metal compound represented by the following general formula;
MaXY(Px)m(Nx)nxe2x80x83xe2x80x83(7)
wherein Ma represents a metal atom belonging to VIII-group metals, X and Y represent each independently hydrogen, halogeno, carboxyl, hydroxide or alkoxy, Px represents phosphine ligand, Nx represents amine ligand, and at least either of Px or Nx is optically active, and m and n are an integer of 1 through 4.
Further, in the preparation process of optically active xcex2-amino alcohols according to the present invention, it is preferable to use a compound represented by the following general formula (8);
Mbmxe2x80x2Znxe2x80x2,
wherein Mb represents either an alikali metal ion or an alkaline earth metal ion, Z represents OHxe2x88x92, ROxe2x88x92, wherein R is C1-6 alkyl, an aromatic anion, HSxe2x88x92 or CO32xe2x88x92, and mxe2x80x2 and nxe2x80x2 are an integer of 1 through 3, as the base described above. However, a quaternary amine salt compound may be used as the base as well.
According to the preparation process of optically active xcex2-amino alcohols of the present invention, optically active xcex2-amino alcohols useful as the intermediate for the synthesis of pharmaceutical active ingredients and agricultural chemicals and represented by the general formula (2) can be prepared highly selectively and at a high yield.
Now, the embodiments for carrying out the present invention are explained in the following.
As the raw material to be used in the process of the present invention, a compound represented by the following general formula (1);
Raxe2x80x94COxe2x80x94CH(Rb)xe2x80x94Rcxe2x80x83xe2x80x83(1)
is used.
In the general formula (1), Ra and Rc each independently represent hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted aralkyl or optionally substituted aryl.
In addition to the groups as described above, any of alkyl, alkenyl, aralkyl and aryl may be used as far as that may give no inhibitory effect on the reactions in the process of the present invention.
As substituents for the optionally substituted alkyl, the optionally substituted cycloalkyl, the optionally substituted alkenyl, the optionally substituted aralkyl and the optionally substituted aryl described above, any ones giving no inhibitory effect on the reactions in the process of the present invention may be used without limitation in terms of substitution position, type of substituent, numbers of substituents, etc.
As examples for the substituents, hydroxy, amino, nitro, alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t-butyl, pentyl and hexyl; alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy and t-butoxy; alkoxycarbonyl, such as methoxycarbonyl, ethoxycabonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl and t-butoxycarbonyl; phenoxycarbonyl, phenyl optionally substituted at the arbitrary position on the benzene ring, naphthyl optionally substituted at the arbitrary position on the naphthalene ring, such as 1-naphthyl and 2-naphthyl, a heterocyclic group optionally substituted at the arbitrary position on the ring, such as furan, pyran, dioxolane, dioxane, pyrrole, thiophene, imidazole, pyrazole, oxazole, isoxazole, triazole, thiazole, isothiazole, pyridine, pyridazine, pyrazine, benzimidazole, benzopyrazole, benzothiazole and quinoline, and halogeno, such as fluorine, chlorine and bromine, may be given.
As examples for the optionally substituted alkyl and cycloalkyl, C1-20 alkyl and C3-8 cycloalkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, may be given.
As examples for the optionally substituted alkenyl, C2-20 alkenyl, such as vinyl, 1-propenyl, 2-propenyl, 1-isopropenyl, 1-butenyl, 1-isopropenyl, 2-butenyl, 3-butenyl, 1,3-butadienyl, 1-pentenyl, 2-pentenyl and 3-pentenyl, may be given.
As examples for the optionally substituted aralkyl described above, C7-20 aralkyl, such as benzyl, xcex1-methylbenzyl, xcex1, xcex1-dimethylbenzyl and xcex1-ethylbenzyl, may be given.
As examples for the optionally substituted aryl described above, an aromatic hydrocarbon, such as 1-naphthyl and 2-naphthyl, an oxygen-containing heterocycle, such as furyl, pyranyl and dioxyolanyl, a sulfur-containing heterocycle, such as thienyl, and a saturated or unsaturated nitrogen-containing heterocycle, such as pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, triazolyl, thiazolyl, isothiazolyl, pyridyl, pyridazyl, pyrazinyl, benzimidazolyl, benzopyrazolyl, benzothiazolyl, quinolyl, antranyl, indonyl and phenanthrenyl, may be given.
Rb represents a group represented by any of the general formulae (3) through (6).
R1CO(R2)Nxe2x80x94xe2x80x83xe2x80x83(3)
R1CO(R1xe2x80x2CO)Nxe2x80x94xe2x80x83xe2x80x83(4)
R1CO(R1xe2x80x2SO2)Nxe2x80x94xe2x80x83xe2x80x83(5)
R1SO2(R2)Nxe2x80x94xe2x80x83xe2x80x83(6)
In the general formulae described above, R1, R1xe2x80x2 and R2 each independently represent hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted aralkyl, optionally substituted aralkyloxy, optionally substituted aryl or optionally substituted aryloxy. Alternatively, R1 and R2 or R1 and R1xe2x80x2 may be united to jointly form a C5-8 membered heterocycle.
As definite examples for R1, R1xe2x80x2 and R2 in the general formulae for Rb described above, hydrogen, C1-10 alkyl and C3-8 cycloalkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, t-pentyl, hexyl, heptyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl,
optionally substituted aryl, such as phenyl, 2-methylphenyl, 2-ethylphenyl, 2-isopropylphenyl, 2-t-butylphenyl, 2-methoxyphenyl, 2-chlorophenyl, 2-vinylphenyl, 3-methylphenyl, 3-ethylphenyl, 3-isopropylphenyl, 3-methoxyphenyl, 3-chlorophenyl, 3-vinylphenyl, 4-methylphenyl, 4-ethylphenyl, 4-isopropylphenyl, 4-t-butylphenyl, 4-vinylphenyl, cumenyl, mesityl, xylyl, 1-naphthyl, 2-naphthyl, anthryl, phenanthryl and indenyl,
optionally substituted C7-10 aralkyl, such as 4-chlorobenzyl and xcex1-methylbenzyl,
C2-10 alkenyl, such as vinyl, allyl and crotyl,
C1-10 alkoxy and C3-8 cycloalkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentyloxy, isopentyloxy, neopentyloxy, t-pentyloxy, hexyloxy, cyclohexyloxy and heptyloxy,
aryloxy, such as phenoxy, 2-methylphenoxy, 2-ethylphenoxy, 2-isopropylphenoxy, 2-t-butylphenoxy, 2-methoxyphenoxy, 2-chlorophenoxy, 2-vinylphenoxy, 3-methylphenoxy, 3-ethylphenoxy, 3-isopropylphenoxy, 3-methoxyphenoxy, 3-chlorophenoxy, 3-vinylphenoxy, 4-methylphenoxy, 4-ethylphenoxy, 4-isopropylphenoxy, 4-t-butylphenoxy, 4-vinylphenoxy, 1-naphthoxy and 2-naphthoxy, and
optionally substituted C7-20 aralkyl, such as benzyloxy, 4-chlorobenzyloxy and 4-methylbenzyloxy, may be given.
Further, R1 and R1xe2x80x2 or R1 and R2 may be united to form a nitrogen-containing heterocycle. As examples for the nitrogen-containing heterocycle, an imide, such as succinimide, maleimide, phthalimide, 1,2-cyclohexane carboximide, 2,4,6-trioxopiperidine and xcex1-pyridone, may be given.
As more definite examples for Rb, acylamino, such as formylamino, acetylamino, propionylamino, butylylamino, isobutylylamino, benzoylamino, 4-methylbenzoylamino, 2-chlorobenzoylamino, 3-methoxybenzoylamino and 2-chloro-4-methylbenzoylamino,
diacylamino, such as diacetylamino and dibenzoylamino,
N-alkyl-N-acylamino, such as N-formyl-N-methylamino, N-acetyl-N-methylamino, N-benzoyl-N-methylamino, N-acetyl-N-ethylamino, N-benzoyl-N-ethylamino, N-acetyl-N-benzylamino, N-benzoyl-N-benzylamino and 4-methylbenzoylmethylamino,
N-aryl-N-acylamino, such as N-acetyl-N-phenylamino, N-acetyl-N-4-methylphenylamino, N-acetyl-N-2-chlorophenylamino, N-acetyl-N-2,4-dichlorophenylamino, N-benzyl-N-phenylamino, N-benzyl-N-4-methylphenylamino, N-benzyl-N-2-chlorophenylamino and N-benzyl-N-2,4-dichlorophenylamino,
alkoxycarbonylamino, such as methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, isopropoxycarbonylamino, n-butoxycarbonylamino and t-butoxycarbonylamino,
aryloxycarbonylamino, such as benzyloxycarbonylamino, phenoxycarbonylamino, 2-methylphenoxycarbonylamino, 3-methylphenoxycarbonylamino, 4-methylphenoxycarbonylamino, 2-methoxyphenoxycarbonylamino, 3-methoxyphenoxycarbonylamino, 4-methoxyphenoxycarbonylamino, 2-chlorophenoxycarbonylamino, 3-chlorophenoxycarbonylamino and 4-chlorophenoxycarbonylamino,
N-alkoxycarbonyl-N-alkylamino, such as N-methoxycarbonyl-N-methylamino, N-ethoxycarbonyl-N-methylamino, N-methoxycarbonyl-N-ethylamino, N-ethoxycarbonyl-N-ethylamino, N-propoxycarbonyl-N-propylamino, N-isopropoxycarbonyl-N-methylamino, N-butoxycarbonyl-N-ethylamino, N-t-butoxycarbonyl-N-methylamino and N-t-butoxycarbonyl-N-butoxyamino,
N-alkoxycarbonyl-N-arylamino, such as N-methoxycarbonyl-N-phenylamino, N-ethoxycarbonyl-N-phenylamino, N-propoxycarbonyl-N-phenylamino, N-isopropoxycarbonyl-N-phenylamino, N-butoxycarbonyl-N-phenylamino and N-t-butoxycarbonyl-N-phenylamino,
alkylsulfonylamino, such as methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, isopropylsulfonylamino, butylsulfonylamino and t-butylsulfonylamino,
N-arylsulfonylamino, such as phenylsulfonylamino, 4-methylphenylsulfonylamino, 2-chlorophenylsulfonylamino and 2,4-dichlorophenylsulfonylamino,
N-alkyl-alkylsulfonylamino and N-alkyl-substituted-phenylsulfonylamino, such as N-methyl-methylsulfonylamino, N-ethyl-methylsulfonylamino, N-propyl-methylsulfonylamino, N-isopropyl-methylsulfonylamino, N-benzyl-methylsulfonylamino, N-butyl-methylsulfonylamino, N-methyl-ethylsulfonylamino, N-ethyl-ethylsulfonylamino, N-methyl-propylsulfonylamino, N-ethyl-propylsulfonylamino, N-methyl-isopropylsulfonylamino, N-ethyl-isopropylsulfonylamino, N-methyl-butylsulfonylamino, N-ethyl-butylsulfonylamino, N-methyl-t-butylsulfonylamino, N-ethyl-t-butylsulfonylamino, N-methyl-phenylsulfonylamino, N-ethyl-phenylsulfonylamino, N-benzyl-phenylsulfonylamino, N-methyl-4-methylphenylsulfonylamino, N-benzyl-4-methylphenylsulfonylamino, N-ethyl-2-chlorophenylsulfonylamino and N-methyl-2,4-dichlorophenylsulfonylamino,
N-aryl-alkylsulfonylamino and N-aryl-substituted-phenylsulfonylamino, such as N-phenyl-methylsulfonylamino, N-phenyl-ethylsulfonylamino, N-phenyl-propylsulfonylamino, N-phenyl-isopropylsulfonylamino, N-phenyl-butylsulfonylamino, N-phenyl-t-butylsulfonylamino, N-phenyl-phenylsulfonylamino, N-phenyl-4-methylphenylsulfonylamino, N-phenyl-2-chlorophenylsulfonylamino and N-phenyl-2,4-dichlorophenylsulfonylamino, and
an imide, such as succinimidoyl, maleimideoyl, phthalimidoyl, 3-methylphthalimidoyl, 4-methylphthalimidoyl, 4-n-butylphthalimidoyl, 4-chlorophthalimidoyl, tetramethylphthalimidoyl, 1,2-cyclohexanecarboximidoyl, 2,4,6-trioxopiperidine-1-yl and xcex1-pyridone-1-yl , may be given.
It is preferable that the optically active transition metal compound used in the process according to the present invention is a homogeneous system optically active hydrogenation catalyst. As the homogeneous system optically active hydrogenation catalyst, it is preferable to use a complex of a transition a metal which belongs to VIII-group of the periodic law table, such as Ru, Rh, Ir and Pt. Such optically active transition metal compounds may be synthesized or obtained according to the process set forth in Angew. Chem. Int. Ed., 37, 1703 (1998) or the like.
It is preferable that the homogeneous system optically active hydrogenation catalyst is one represented by the following general formula (7);
MaXY(Px)m(Nx)nxe2x80x83xe2x80x83(7)
wherein Ma represents a metal atom belonging to VIII-group, X and Y each independently represent hydrogen, halogeno, hydroxy or alkoxy, Px represents phosphine ligand, Nx represents amine ligand, provided that at least either Px or Nx is optically active, and m and n each independently represent 0 or an integer of 1 through 4.
In the general formula (7), it is preferable that Ma is a metal belonging to VIII-group, such as Ru, Rh, Ir and Pt. In particular, it is most preferable that Ma is a complex of Ru in view of stability of the complex and the supply availability.
In the general formula (7), X and Y each independently represent an anionic group including hydrogen, halogeno, such as fluorine, chlorine and bromine, hydroxy, alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy and butoxy.
As Px as a phosphine ligand, unidentate ligand of phosphorus represented by a general formula of PRARBRC, bidentate ligand of phosphorus represented by a general formula of RDREPxe2x80x94Wxe2x80x94PRFRG and the like may be given.
In the general formula PRARBRC, RA, RB and RC each independently represent alkyl, optionally substituted phenyl, cycloalkyl or the like, or alternatively any two of RA, RB and RC may be united to form an optionally substituted alicycle group.
When the phosphorus compound represented by the general formula of PRARBRC is optically active, at least one of RA, RB and RC is optically active or phosphorus atom substituted with three different substituents is optically active.
In the general formula of RDREPxe2x80x94Wxe2x80x94PRFRG, RD, RE, RF and RG each independently alkyl, optionally substituted phenyl or cycloalkyl, or alternatively RD and RE or RF and RG may be united to form optionally substituted alicyclic group. W represents C1-10 hydrocarbon, cyclohydrocarbon, aryl, unsaturated hydrocarbon or the like.
As examples for the unidentate ligand represented by the general formula of PRARBRC described above, a tertiary phosphine, such as trimethylphosphine, triethylphosphine, tributylphosphine, triphenylphosphine, tricyclohexylphosphine, tri(p-tolyl)phosphine, diphenylmethylphosphine, dimethylphenylphosphine, isopropylmethylphosphine, cyclohexyl(O-anisyl)-methylphosphine, 1-[2-(diphenylphosphino)ferrocenyl]ethyl methyl ether and 2-(diphenylphosphino)-2xe2x80x2-methoxy-1,1xe2x80x2-binaphthyl, may be preferably given. Further, a phosphine ligand represented by the general formula of PRARBRC wherein the substituents for RA, RB and RC are different groups from one another may be used as well.
As examples for the racemic or optically active bidentate phosphine ligand represented by the general formula of RDREPxe2x80x94Wxe2x80x94PRFRG described above, bidentated tertiary phosphine, such as bis-diphenylphosphinomethane, bis-diphenylphosphinoethane, bis-diphenylphosphinopropane, bis-diphenylphosphinobutane, bis-dimethylphosphinoethane, and bis-dimethylphosphinopropane, and the like may be preferably given.
Further, as examples for the commercially available bidentate phosphine ligand, BINAP: 2,2xe2x80x2-bis-(diphenylphosphino)-1,1xe2x80x2-binaphthyl, BINAP derivative containing a substituent, such as alkyl and aryl, on the naphthyl ring, BINAP derivative containing 1-5 substituents, such as alkyl, on the benzene ring bonding to a phosphorus atom, such as H8BINAP and BINAP, Xylyl-BINAP: 2,2xe2x80x2-bis-(di-3,5-xylylphosphino)-1,1xe2x80x2-binaphthyl), BICHEP: 2,2xe2x80x2-bis-(dicyclohexylphosphino)-6,6xe2x80x2-dimethyl-1,1xe2x80x2-biphenyl, BPPFA: 1-[1xe2x80x2, 2-bis-(diphenylphosphino)ferrosenyl]ethyldiamine, CHIRAPHOS 2,3-bis-(diphenylphosphino)butane, CYCPHOS: 1-cyclohexyl-1,2-bis-(diphenylphosphino)ethane, DEGPHOS: 1-substituted-3,4-bis(diphenylphosphino)pyrrolidine, DIOP: 2,3-O-isopropylpyridene-2,3-dihydroxy-1,4-bis-(diphenylphosphino)butane, DIPAMP: 1,2-bis[(O-methoxyphenyl)phenylphosphino]ethane, DuPHOS: (Substituted-1,2-bis(phosphorano)benzene), NORPHOS: 5,6-bis-(diphenylphosphino)-2-norbornene, PNNP: N,Nxe2x80x2-bis-(diphenylphosphino)-N,Nxe2x80x2-bis-[1-phenylethyl]ethylene diamine, PROPHOS: 1,2-bis-(diphenylphosphino)propane, KEWPHOS: 2,4-bis-(diphenylphosphino)pentane, and the like may be given. In addition, BINAP derivatives substituted with fluorine-containing substituent and the like may be used as well. There is no limitation for the phosphine ligand to be used in the present invention as far as it may stably form a metal complex.
As the amine ligand represented by Nx, a nitrogen-containing unidetate ligand represented by a general formula of NRHRIRJ, a diamine ligand represented by a general formula of RKRLNxe2x80x94Xxe2x80x94NRMRN and the like may be used.
In the general formula, NRHRIRJ described above, RH, RI and RJ each independently represent hydrogen, alkyl, aryl or unsaturated hydrocarbon, or alternatively any two of RH, RI and RJ may be united to jointly form an optionally substituted alicyclic group. Further, at least one of RH, RI and RJ may be an optically active group.
In the general formula of RKRLNxe2x80x94Xxe2x80x94NRMRN described above, RK, RL, RM and RN each independently represent hydrogen, alkyl, aryl or unsaturated hydrocarbon, or alternatively RK and RL or RM and RN may be united to jointly form an optionally substituted alicyclic group or a nitrogen-containing heterocycle, and X represents C1-5 alkyl, cycloalkyl ary or unsaturated hydrocarbon.
As examples for the monoamine ligand represented by the general formula of NRHRIRJ described above, monoamine compounds, such as methylamine, ethylamine, propylamine, butylamine, pentylamine, hexylamine, cyclopentylamine, cyclohexylamine, benzylamine, dimethylamine, diethylamine, dipropylamine, dihexylamine, dicyclopentylamine, dicyclohexylamine, dibenzylamine, diphenylamine, phenylethylamine, proline and piperidine, may be given. In addition thereto, optically active monoamine compounds, such as optically active phenylethylamine, naphthylethylamine, cyclohexylamine and cycloheptylethylene diamine, may be examples for the optically active monoamine ligand.
As examples for the diamine ligand represented by the general formula of RKRLNxe2x80x94Xxe2x80x94NRMRN described above, methylene diamine, ethylene diamine, 1,2-diaminopropane, propylene diamine, 1,3-diaminopropane, 1,4-diaminobutane, 2,3-diaminobutane, 1,2-cyclopentane diamine, 1,2-cyclohexane diamine, N-methyl ethylene diamine, N,Nxe2x80x2-dimethyl ethylene diamine, N,N,Nxe2x80x2-trimethyl ethylene diamine, N,N,Nxe2x80x2,Nxe2x80x2-tetramethyl ethylene diamine, o-phenylene diamine, p-phenylene diamine and the like may be given. Furthermore, optically active diamines may be used as the diamine ligand as well.
As examples for the optically active diamine compounds described above, 1,2-diphenyl ethylene diamine, 1,2-cyclohexane diamine, 1,2-cycloheptane diamine, 2,3-dimethylbutane diamine, 1-methyl-2,2-diphenyl ethylene diamine, 1-isobutyl-2,2-diphenyl ethylene diamine, 1-isopropyl-2,2-diphenyl ethylene diamine, 1-methyl-2,2-di(p-methoxyphenyl)ethylene diamine, 1-isobutyl-2,2-di(p-methoxyphenyl)ethylene diamine, 1-isopropyl-2,2-di(p-methoxyphenyl)ethylene diamine, 1-benzyl-2,2-di(p-methoxyphenyl) ethylene diamine, 1-methyl-2, 2-dinaphthyl ethylene diamine, 1-isobutyl-2,2-dinaphthyl ethylene diamine, 1-isopropyl-2,2-dinaphthyl ethylene diamine and the like may be given.
The optically active diamine compounds usable in the process of the present invention are not limited to the optically active diamine derivatives as described above, and optically active derivatives of propane diamine, butane diamine, phenylene diamine, cyclohexane diamine and the like may be used as well. There is no limitation for the amine ligand to be used in the process of the present invention as far as it can stably form a metal complex.
In the present invention, the amount of the homogeneous system optically active hydrogenation catalyst to be used in the process shall differ depending upon the type of the reaction substrate, reaction container, economical condition, etc., however, the amount is normally in a range of from 1/100 to 1/10,000,000 as a molar ratio relative to a carbonyl compound as the reaction substrate, and more preferably in a range of from 1/200 to 1/100,000 as a molar ratio.
As the base used in the process of the present invention, it is preferable to use a compound represented by a general formula (8);
Mbmxe2x80x2Znxe2x80x83xe2x80x83(8)
wherein Mb represents an alkali metal ion or an alkaline earth metal ion, Z represents OHxe2x88x92, ROxe2x88x92, wherein R represents C1-6 alkyl, an aromatic anion, HSxe2x88x92 or CO32xe2x88x92, and mxe2x80x2 and nxe2x80x2 represent an integer of 1 through 3.
As examples for the base described above, KOH, KOCH3, KOCH(CH3)2, KOC(CH3)3, KC10H8, NaOH, NaOCH3, LiOH, LiOCH3, LiOCH(CH3)2, Mg(OC2H5)2, NsSH, K2CO3, Cs2CO3 and the like may be given. In addition, quaternary ammonium compounds may be also used as the base in the process of the present invention.
The amount of the base to be used in the process is normally 0.5 equivalent or more relative to the amount of the optically active transition metal compound, and more preferably 2 equivalents or more, when appropriate.
The reaction in the process of the present invention is carried out by dissolving a substrate, which is an xcex1-aminocarbonyl compound represented by the general formula (1), into an inactive solvent and applying hydrogen or a hydrogen donor for the reaction in the presence of an optically active transition metal compound and a base in a prefixed amount.
As the solvent usable in the reaction, any solvent which is inactive and capable of dissolving the reaction material (substrate) and a catalyst may be used without limitation. As examples for the solvent, an aromatic hydrocarbon, such as benzene, toluene and xylene, an aliphatic hydrocabon, such as pentane, hexane and octane, halogen-containing hydrocarbon, such as methylene chloride, chloroform and carbon tetrachloride, an ether, such as ether and tetrahydrofuran, an alcohol, such as methanol, ethanol, 2-propanol, butanol and benzyl alcohol, and an organic solvent containing hateroatom, such as acetonitrile, DMF (N,N-dimethylformamide), N-methyl pyrrolidone, pyridine and DMSO (domethylsulfoxide), may be given.
Among the examples for the solvent described above, it is particularly preferable to use an alcohol since the desired reaction product is an alcohol. Although the exampled solvent alone is usable, the solvents may be used in combination as well.
The amount of the solvent used in the reaction is determined in connection with the solubility of the reaction substrate and economical condition. For example, when 2-propanol is used as the solvent, the reaction may be proceeded at the substrate concentration range of from lower than 1% to almost no solvent condition, however, the solvent is preferably used at a concentration range of from 20 to 50 wt %.
The reaction is carried out in the presence of either hydrogen gas or a hydrogen donor. When hydrogen gas is used, it is preferable to maintain hydrogen pressure in the reaction system within a range of from 1 to 200 atmospheric pressure, and more preferably from 3 to 100 atmospheric pressure. As examples for the hydrogen donor described above, hydride complex, hydrogen occluded alloy and the like may be given.
The reaction temperature should be maintained in a range of from xe2x88x9230 to 200xc2x0 C. while paying attention to the reaction speed, and more preferably in a range of from 15 to 100xc2x0 C. The reaction is normally completed in a period of from several minutes to 10 hours depending upon the reaction condition, such as reaction substrate concentration, temperature and pressure.
Besides, when producing the optically active amino alcohol represented by the general formula (2) in an industrial scale, the reaction may be carried out by either batch system or continuous system.
The examples for the compounds represented by the general formula (2) to be produced according to the process of the present invention and the starting material compounds represented by the general formula (1) are shown in the following table.
In the table below, Et represents ethyl, Pr represents propyl, Bu represents butyl and Ph represents phenyl. 
Now, the present invention is further explained in detail with referring the following examples.